Amid Withdrawal News, Final DREAMM-2 Analysis Confirms Durability of Belantamab Mafotodin Monotherapy in Relapsed/Refractory Multiple Myeloma

Single-agent belantamab mafodotin (Blenrep) continued to produce rapid, deep, and durable responses in patients with relapsed/refractory multiple myeloma, according to the results of the final analysis of the phase 2 DREAMM-2 trial (NCT03525678).¹

Final results from the phase 2 two arm, open-label study of single-agent belantamab showed a median time to response of 1.5 months (95% CI, 1.0-2.1) in the cohort of patients given 2.5 mg/kg of belanatamab (n = 97) compared with 1.4 months in the 3.4 mg/kg cohort (n = 99). Moreover, median duration of response (DOR) was 12.5 months (95% CI, 4.2-19.3) in the 2.5 mg/kg cohort and 6.2 (95% CI, 4.8-18.7) in the 3.4 mg/kg cohort.

The median DOR in the 2.5 mg/kg was an improvement over previous reposts and the 2.5 mg/kg dose of belantamab remains the only recommended dose of the antibody-drug conjugate, explained Ajay Nooka, MD, MPH, FACP, in a presentation of the data at the 2022 ASH Annual Meeting. The final analysis showed that overall survival (OS) also improved from previous studies for patients on the 2.5 mg/kg dose, while the overall response rate (ORR), clinical benefit response (CBR), and DOR were maintained across patient subgroups with HR-cytogenetic and mild-to-moderate renal impairment.

In comparison to the 2020 13-month analysis that first looked at belanatamab alone in patients with RRMM,² the OS improved to over 15 months in certain patients with a median OS of 15.3 months (95% CI, 9.9,18.9) and 30.7 months in patients who just had a very good partial response (VGPR) to the drug. The ORR remained consistent with previous reports at 32% in the 2.5 mg/kg cohort (97.5% CI, 21.7%-43.6%) compared with 35% (97.5% CI, 24.8%-47.0%) in the 3.5 mg/kg cohort but there were more complete responses, factoring for stringent CR, in the analysis cohort vs the comparing arm at 9 vs 5 patients, respectively. Moreover, 9 patients had a VGPR, 13 had a partial response, and 27 had stable disease at the time of follow up.

For patients who had a VGPR or greater the median progression-free survival (PFS) was 14.0 months (95% CI, 9.7 to not reached [NR]) in the 2.5 mg/kg cohort compared with 16.8 months (95% CI, 7.7-NR) in the 3.4 mg/kg cohort. Median PFS among the rest of the patients was 2.8 months (95% CI, 1.6-3.6 months) in the 2.5 mg/kg cohort compared with 3.9 months (95% CI, 2.0-5.8) in the 3.4 mg/kg arm.

The minimal residual disease (MRD) negativity rates also remained consistent with previous reports but were ultimately stronger in the 2.5 mg/kg cohort. The MRD negativity rate for patients with a VGPR or more was 36% (95% CI, 12.8%-64.9%) in the 2.5 mg/kg cohort vs 23% (95% CI, 5.0%-53.8%) in the 3.4 mg/kg cohort. Among the 14 patients with a VGPR in the 2.5 mg/kg cohort 5 were MRD-negative compared to 3 patients out of 13 patients with VGPR in the 3.5 mg/kg cohort.

The DREAMM-2 data follow the November 2022 news that GlaxoSmithKline, the developer of belantamab mafodotin, announced that it had initiated the process for withdrawal of the US marketing authorization for the agent based on a request from the FDA. This was based on the results of the phase 3 DREAMM-3 trial, which missed the requirements of its accelerated approval regulations.³

In DREAMM-2, 221 patients were enrolled with the median age of patients randomized to treatment being 65 years old in the 2.5 mg/kg cohort compared with 67 years old in the 3.4 mg/kg cohort. Eligible patients for the trial had to have measurable disease and refractory to immunomodulatory drugs, proteasome inhibitors, and intolerant to anti-CD38 monoclonal antibodies. Moreover, patients could not have been exposed to prior BCMA-targeted therapy.

“No new safety signals were noted [when] comparing [results] with the earlier portion of the study,” explained Nooka, director of the Myeloma program in the department of hematology and medical oncology at the Emory University School of Medicine, in his presentation. “The most commonly reported any grade ocular adverse events [AEs] in both cohorts included keratopathy, blurred vision, and the best corrected visual acuity [BCVA], or BCVA reduced to 20/50 or worse.”

Overall, 71% of patients in the 2.5 mg/kg cohort had keratopathy compared with 75% in the 3.5 mg/kg cohort with 29% having grade 3 keratopathy and 1 patient experiencing grade 4 keratopathy vs 24% and 1 patient with a grade 4 event in the 3.4 mg/kg cohort. Blurred vision was seen in 25% of patients in 2.5 mg/kg cohort vs 36% in the 3.4 mg/kg cohort and 48% of patients experienced BCVA reduced to 20/50 or worse vs 49%, respectively.

The other 2 most frequent AEs of any grade in the 2.5 mg/kg vs 3.4 mg/kg cohorts was thrombocytopenia (38% vs 57%) and anemia (27% vs 38%). In the 2.5 mg/kg arm 9 patients experienced grade 3 thrombocytopenia and 21 patients had grade 3 anemia compared with 9 patients 3.4 mg/kg cohort and 38 with anemia, respectively.

The overall infection rate was lower in the 2.5 mg/kg cohort at 45% compared with 55% in the 3.4 mg/kg cohort with 19 patients in the 2.5 mg/kg arm experiencing grade 3 or greater infections vs 44 patients in the 3.4 mg/kg arm. The most frequent of these infections in both cohorts were upper respiratory tract infections seen in 10 patients in the 2.5 mg/kg arm compared with 22 patients in the 3.4 mg/kg arm. Serious AEs were also seen in the final analysis with 45% of patients in the 2.5 mg/kg cohort experiencing them and 4 patients having a fatal serious AE with 1 being determined to have been treatment related.

These ocular and other AEs were then managed with dose delays and dose reductions with 54% of patients in the 2.5 mg/kg cohort having an AE related dose delay with 15 patients having 3 or more dose delays. Moreover, in responding patients (n = 31) dose delays of 63 days or longer occurred in 16 patients. However, in the 3.4 mg/kg cohort 62% of patients had an AE related dose delay with 20 patients having more than 3 dose delays. In the 34 responding patients in the 3.4 mg/kg cohort 19 patients had a dose delay of 63 days or more.

For the patients who had dose delays of 63 days or greater response was maintained to therapy. Among patients who had any keratopathy-related dose delays 34 patients in the 2.5 mg/kg cohort and 39 in the 3.5 mg/kg cohort ultimately restarted treatment. Moreover, the median time to resolution of the first event of either blurred vision, reduced BCVA and keratopathy was 43, 23, and 120 days, respectively, in the 2.5 mg/kg arm. However, keratopathy was not resolved for 18 patients in the 2.5 mg/kg cohort compared with 27 patients in the 3.4 mg/kg arm.

Overall, AE related dose reductions occurred in 36% and 44% of patients in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively, with ocular AE related dose reductions and dose delays occurring in slightly more patients in the 3.4 mg/kg cohort vs the 2.5 mg/kg cohort relating to keratopathy at 28% vs 30% and 47% vs 49%, respectively. Ocular AEs that led to permanent discontinuations occurred in 5 patients in the 2.5 mg/kg cohort compared with 3 patients in the 3.4 mg/kg cohort with 11 patients overall discontinuing belantamab treatment due to AEs in the 2.5 mg/kg cohort vs 12 in the 3.5 mg/kg cohort.

According to Nooka, despite the frequency of AEs and occurrence of ocular AEs these did not impact the overall patient’s health related quality of life. Therefore, he concluded that 2.5 mg/kg of belantamab given every 3 weeks resulted in rapid, deep, and durable responses for patients with RRMM.

References

1. Nooka A, Cohen A, Lee, H, et al. Single-Agent Belantamab Mafodotin in Patients with Relapsed or Refractory Multiple Myeloma: Final Analysis of the DREAMM-2 Trial. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 3246.
2. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020 Feb;21(2):207-221. doi: 10.1016/S1470-2045(19)30788-0
3. GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News release. GlaxoSmithKline. November 22, 2022. Accessed December 12, 2022. http://bit.ly/3gniPi1